The long-term objective of the proposed research is to combine pharmaceutical and biochemical knowledge in order to develop a new approach to increasing drug product efficacy. The specific objective of the proposed research is to increase the absorption rate of water insoluble drugs through utilization of membrane metabolism. Water insoluble drugs are often poorly and/or erratically absorbed leading to less than optimum therapeutic response. Two factors can be responsible: slow dissolution rate and/or slow absorption. Solubilizing derivatives, while increasing dissolution rate generally are not as effective in increasing absorption rate due to the conflicting requirements of transport through a composite (polar/nonpolar) barrier. In this case, increasing aqueous solubility generally decreases the effective permeability through the nonpolar phase of the membrane. This inevitable compromise can be overcome by utilizing the metabolic reactions that occur in the interfacial (brush border) region between the polar and nonpolar membrane phases. For insoluble drugs, the strategy is to make soluble derivatives for dissolution and aqueous diffusion purposes but which in the brush border region are metabolically converted to the form desirable for membrane (nonpolar phase) permeation. For this project, derivatives of both polar and nonpolar compounds will be made and their membrane permeation rates in an intestinal perfusion system determined. In this manner the following specific questions will be answered: 1) what is the maximum permeation rate and how does it depend on the drug and derivatizing group properties, 2) is the process saturable and/or inhibited by protease or peptide transport inhibitors, 3) how advantageous is this approach over other solubilizing approaches, and 4) how successful can the approach be in whole animals and what is the effect of homogenous enzymes and food? The specific problems investigated in this project are but examples of problems that may be solved by combining pharmaceutical and biochemical knowledge. This general approach, based on biochemical and pharmaceutical knowledge, suggests a class of drugs that are metabolically activated. By combining these two areas of knowledge more effective and efficacious therapeutic agents can be designed.